1. Nephrotic Syndrome and Proteinuria
A small amount of protein is found in the urine of healthy children (<4 mg/m2/hour or UPr/Cr < 0.2). Nephrotic proteinuria in children is defined as protein greater than 40 mg/m2/hour or first-morning urine protein/creatinine greater than 2.0. Proteinuria between these two levels is mildly to moderately elevated, but not nephrotic.

2. Nephrotic syndrome (NS) is characterized by
persistent heavy proteinuria (mainly albuminuria) (>2 g/m2/24 hours);
hypoproteinemia (serum albumin <3.0 g/dL); hypercholesterolemia (>250 mg/dL); and edema.
It is not at all uncommon to find individuals with clear evidence of nephrotic-range proteinuria and mild to moderate hypoalbuminemia in whom evidence of hypolipidemia and peripheral edema are minimal.

5. Causes of Childhood Nephrotic Syndrome
IDIOPATHIC NEPHROTIC SYNDROME   
1- Minimal change disease N.S   
2- Focal segmental glomerulosclerosis   
3-Membranous nephropathy

6. Finnish-type congenital nephrotic syndrome
SECONDARY CAUSES
Infections  
  Hepatitis B,C   
HIV1    Malaria    Syphilis    Toxoplasmosis
Drugs    Penicillamine    Gold    Nonsteroidal anti-inflammatory drugs    Pamidronate    Interferon    Mercury

7. Etiology&pathogenesis MCNS
Age, race, and geography affect the incidence of nephrotic syndrome. Certain HLA types (HLA-DR7, HLA-B8, and HLA-B12) are associated with an increased incidence of nephrotic syndrome.
The primary disorder is an increase in glomerular permeability to proteins,most likely as result of the loss of the glomerular basement membrane sialoproteins.

8. Massive proteinuria results and leads to a decline in serum proteins, especially albumin. Plasma oncotic pressure is diminished, resulting in a shift of fluid from the vascular to the interstitial compartment and a contraction in plasma volume.

9. Edema formation is enhanced by a reduction ineffective blood volume and by an increase in tubular sodium chloride reabsorption secondary to activation of the renin-angiotensin-aldosterone system

10. Type
1-Minimal change nephrotic syndrome (MCNS) is the most common histologic form of nephrotic syndrome, seen in 70% to 80% of cases age<7yrs.
Males are affected more frequently than females by a 2 : 1 ratio.
Most children younger than 7 years
Children7-16years old have 50% chance of having MCNS.

11. Pathology
In minimal change nephrotic syndrome (MCNS) (about 85% of total cases of nephrotic syndrome in children).
the glomeruli appear normal or show a minimal increase in mesangial cells and matrix.
Findings on immunofluorescence microscopy are typically negative.
Electron microscopy simply reveals effacement of the epithelial cell foot processes.
More than 95% of children with minimal change disease respond to corticosteroid therapy.

12. 2-The initial presentation of focal segmental glomerulosclerosis (FSGS) is usually identical to that of MCNS
A circulating factor that increases glomerular permeability to albumin is found in some patients with FSGS.
FSGS accounts for approximately 10% of children with nephrotic syndrome.
It is usually steroid resistance.

13. 3-Membranoproliferative glomerulonephritis (MPGN) is characterized by
hypocomplementemia with signs of glomerular renal disease.
MPGN is present in 5% to 15% of children with primary NS,
It is typically persistent, and has a high likelihood of progression to renal failure over time.

14. 4-Membranous nephropathy is infrequent in childhood
4-Membranous nephropathy is infrequent in childhood. Approximately 1% of children with nephrotic syndrome have this lesion on a kidney biopsy specimen. It is seen most commonly in adolescents and children with systemic infections, such as hepatitis B, syphilis, malaria, and toxoplasmosis, or receiving drug therapy (gold salts, penicillamine). Hematuria is common.

15. edema, low birth weight, large placenta proteinuria, hematuria
4-Congenital nephrotic syndrome is defined as clinical nephrotic syndrome that presents during the first 2 months of life . There are two common types.
The Finnish type is an autosomal recessive disorder most common in persons of Scandinavian
edema, low birth weight, large placenta
proteinuria, hematuria
death within 2 years of age
Aggressive medical therapy of familial congenital nephrotic syndrome, with early nephrectomy, dialysis, and subsequent transplantation, is the only effective approach to this syndrome.

16. Clinical Manifestations MCNS
the major clinical manifestation is edema, periorbital, scrotal, and labial regions , Ultimately, it becomes generalized, with the development of ascites, pleural effusions, and genital edema. and can be massive (anasarca). It is pitting in nature . anorexia, irritability, fatigue, abdominal discomfort, and diarrhea are common.
respiratory distress is not uncommon.
Infection is a major complication in children with NS. An increased incidence of serious infections, particularly bacteremia and peritonitis (particularly Streptococcus pneumoniae, Escherichia coli, or Klebsiella), is due to urinary loss of immunoglobulins and complement.

18. Typical MCNS is defined as the absence of
persistent hematuria,
renal insufficiency (elevated BUN and creatinine, oliguria),
hypertension,
hypocomplementemia.
RBC cast

19. A diagnosis other than MCNS should be considered in the presence of
age <1 yr or >8yr
family history kidney disease
extrarenal findings (arthritis, rash, anemia)
hypertension or pulmonary edema, acute or chronic renal insufficiency
gross hematuria.
A low level of C3 implies the presence of a lesion other than MCNS and a renal biopsy is indicated before a trial of steroid therapy.

20. DIAGNOSTIC STUDIES Serum C3-normal
Proteinuria of 3+ or greater on two to three random urine specimen .or>40mglm2lhr.
The preferred method is a urine protein-to-creatinine ratio on a random sample >2.
The normal ratio generally is less than 0.2 when measured on the first morning specimen
hypoalbuminemia and hypercholesterolemia,
Serum C3-normal
If C3 levels are low, a renal biopsy may be indicated before a trial of steroid therapy

21. Evaluation of a Child with Proteinuria
Complete history and physical examination
Confirmation of presence of proteinuria by repeat urinalysis
First morning urine sample for total protein and creatinine (if ratio of protein to creatinine is >0.5, continue with steps 4-6)
Measurement of levels of serum electrolytes, BUN, creatinine (calculate creatinine clearance), total protein, albumin, and cholesterol
Measurement of streptozyme, C3, C4, ANA
Renal ultrasonography

22. Differential Diagnosis Prteinurea
1-Transient proteinuria is seen after vigorous exercise and occasionally in febrile or dehydrated children ,cold exposure, heart failure, seizures, or stress. The proteinuria usually does not exceed 1+2+ on the dipstick. No evaluation or therapy is needed for children with this benign condition.

23. 2-Postural (orthostatic) proteinuria is a benign condi-tion defined by normal protein excretion while patients are re-cumbent &significant proteinuria when they are upright in healthy children

24. Glomerular proteinuria is classified by its degree.
Intermittent (mild) proteinuria (<0.5 g/m2/day) is seen in pyelonephritis, renal cystic diseases, obstructive uropathies, and mild glomerulonephritis.
Moderate proteinuria (0.5 to 1 g/m2/day) is seen in acute post-streptococcal glomerulonephritis, mild Henoch-Schönlein nephritis, severe pyelonephritis, chronic glomerulonephritis, and hemolytic uremic syndrome (HUS).
Severe proteinuria (>1 g/m2/day) is characteristically associated with nephrotic syndrome

25. What are the typical clinical features and therapeutic responses seen in patients with MCNS?
Edema is generally present, blood pressure is normal, and gross hematuria is absent, but up to one third of these patients may have microscopic hematuria; however, RBC casts are not seen. In the absence of significant intravascular volume depletion, BUN, creatinine, and electrolytes are all within normal limits. Children who present symptoms in this manner should be started on daily prednisone; this is often called a "medical biopsy."

26. DDx The differential diagnosis of the child with marked edema includes
1-protein-losing enteropathy,
2-hepatic failure,
3-congestive heart failure,
4- acute or chronic glomerulonephritis,
5- protein malnutrition.

27. Treatment
With good parental and patient education and close outpatient follow-up care, hospitalization is not usually necessary. Hospitalization should be considered if a patient has generalized edema severe enough to cause respiratory distress, if a patient has tense scrotal or labial edema, if he or she has complications (eg, bacterial sepsis, peritonitis, pneumonia, thromboembolism, failure to thrive), or if patient or family compliance with treatment is in doubt.

28. Diuretics will be needed; furosemide (1 mg/kg/d) and spironolactone (2 mg/kg/d) will help when fluid retention is severe, provided no signs of renal failure or volume contraction are evident. Achieving a satisfactory diuresis is difficult when the patient's serum albumin level is less than 1.5 g/dL.
Albumin at 1 g/kg may be given, followed by intravenous furosemide. Complications may occur, including pulmonary edema.

29. Some evidence suggests that albumin may delay the response to steroids and may even induce more frequent relapses, probably by causing severe glomerular epithelial damage.
Fluid removal and weight loss remain transient unless proteinuria remits.

30. With regard to infection, oral penicillin can be prescribed as prophylaxis for children with gross edema. Abdominal paracentesis should be performed if the patient develops signs of peritonitis, and any bacterial infection should be treated promptly.
A nonimmune patient with varicella should receive zoster immunoglobulin therapy if exposed to chickenpox, and acyclovir should be given if the patient develops chickenpox.

31. Specific therapy Initial management
oral prednisone or prednisolone is started in a dosage of 2 mg/kg/day (60 mg/m2/d) (after confirming a negative PPD test and administering the polyvalent pneumococcal vaccine) . given daily for 4-6 weeks. Single daily is effctive as split
doses and less side effect.
An initial 6-wk course of daily steroid treatment leads to a significantly lower relapse rate than previously recommended shorter courses of daily therapy.

32. Approximately 90% of patients with MCNS respond to this therapy with complete clearing of proteinuria, but only about 20% of children with FSGS
The majority of children with MCNS will respond between the 10th and 14th days of such therapy,

33. Children who do not respond (ie, complete clearing proteinuria>8wks) should be referred to a pediatric nephrologist for percutaneous renal biopsy and consideration be given to an alternative plan of treatment.

34. After the initial 6-wk course, the prednisone dose should be tapered to 40 mg/m2/day given every other day as a single daily dose for at least 4 wk. The alternate-day dose is then slowly tapered and discontinued over the next 1-2 mo.
There is evidence that both an increased dose of steroids and a prolonged duration of therapy are important factors in reducing the risk of relapse.

35. Children who continue to have proteinuria (2+ or greater) after 8 wk of steroid therapy are considered
steroid resistant, and a diagnostic renal biopsy should be performed

36. Steroid-dependent patients, frequent relapsers, and steroid-resistant patients may be candidates for alternative agents(secondary therapies ).
Cyclophosphamide
Cyclosporine

37. steroid dependent, patients relapse while on alternate-day steroid therapy or within 28 days of completing a successful course of prednisone therapy.
Patients who respond well to prednisone therapy but relapse ≥4 times in a 12-mo period are termed frequent relapsers. Children who fail to respond to prednisone therapy within 8 wk of therapy are termed steroid resistant.

38. Relapses should be treated with 60 mg/m2/day (80 mg daily max) in a single A.M dose until the child enters remission (urine trace or negative for protein for 3 consecutive days). The prednisone dose is then changed to alternate-day dosing as noted with initial therapy, and gradually tapered over 4-8 wk.

39. Complications
1-Bacteremia and peritonitis may occur, particularly with Streptococcus pneumoniae or Escherichia coli.
2-Hypovolemia may be the result of diarrhea or use of diuretics
3-The loss of proteins may lead to a hypercoagulable state with a risk of thromboembolism (renal vein thrombosis,pulmonary embolism)
4-Immunosuppression-related toxicity
5-Acute renal failure
6-Stroid intoxication (

40. Prognosis
Nearly 80% of children with MCNS experience a relapse of the proteinuria at some point, defined as heavy proteinuria that persists for 3 to 5 consecutive days.
Most children with nephrotic syndrome eventually go into remission.
Transient (1 to 2 days) proteinuria may occur with an intercurrent infection in children with MCNS and is not considered a relapse.
Steroid therapy usually is rapidly effective for a true relapse. Patients with MCNS who respond to steroid therapy have little risk of chronic renal failure.

41. Patients with FSGS may be initially responsive to steroids, but become late nonresponders. Many children with FSGS progress to end-stage kidney failure

42. When should secondary therapies be considered for MCNS?
For patients who do not respond to the initial course of prednisone
For patients who become subsequent nonresponders to prednisone during relapses
For patients who have frequent relapses
For patients who develop significant side effects from steroids

43. In which children with nephrotic syndrome should renal biopsy be considered?
1-Because older children are more likely to have other forms of nephrotic syndrome (e.g., focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis), most pediatric nephrologists would biopsy those who present symptoms at the age of >8 years before beginning therapy.
2- Certainly the presence of significant hypertension, renal insufficiency, RBC casts, multiple organ involvement, partial lipodystrophy, or a low serum C3 level all speak against the finding of MCNS and require a renal biopsy for definitive diagnosis.
3- Children of any age who do not go into remission during their initial course of prednisone or who fail to respond to prednisone after relapses will also require a renal biopsy

45. Thank You